Treatment of erectile dysfunction and other indications

ABSTRACT

The present invention generally relates to the transdermal delivery of various compounds. In some aspects, transdermal delivery may be facilitated by the use of a hostile biophysical environment. One set of embodiments provides a composition for topical delivery comprising a phosphodiesterase type 5 inhibitor and/or a salt thereof, and optionally, a hostile biophysical environment and/or a nitric oxide donor. In some cases, the composition may be stabilized using a combination of a stabilization polymer (such as xanthan gum, KELTROL® BT and/or KELTROL® RD), propylene glycol, and a polysorbate surfactant such as Polysorbate 20, which combination unexpectedly provides temperature stability to the composition, e.g., at elevated temperatures such as at least 40° C. (at least about 104° F.), as compared to compositions lacking one or more of these.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/427,999, filed Dec. 29, 2010, entitled“Treatment of Erectile Dysfunction and Other Indications,” by E. T.Fossel; and of U.S. Provisional Patent Application Ser. No. 61/428,213,filed Dec. 29, 2010, entitled “Methods and Compositions for PreparingEmulsions for Topical Drug Delivery,” by E. T. Fossel. Each of these isincorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention generally relates to transdermal delivery and, inparticular, to the transdermal delivery of phosphodiesterase type 5inhibitors and other compounds.

BACKGROUND

Phosphodiesterase type 5 inhibitors are drugs used to block thedegradative action of phosphodiesterase type 5 on cyclic GMP in thesmooth muscle cells lining the blood vessels supplying the corpuscavernosum of the penis. These drugs are commonly used in the treatmentof erectile dysfunction.

Phosphodiesterase type 5 inhibitors are commonly delivered orally.Currently, no transdermal formulations of phosphodiesterase type 5inhibitors have been approved by the FDA. Accordingly, systems andmethods for transdermally delivering clinically useful amounts ofphosphodiesterase type 5 inhibitors are needed.

SUMMARY OF THE INVENTION

The present invention generally relates to the transdermal delivery ofphosphodiesterase type 5 inhibitors and other compounds. The subjectmatter of the present invention involves, in some cases, interrelatedproducts, alternative solutions to a particular problem, and/or aplurality of different uses of one or more systems and/or articles.

Several methods are disclosed herein of administering a subject with acomposition for prevention or treatment of a particular condition. It isto be understood that in each such aspect of the invention, theinvention specifically includes, also, the composition for use in thetreatment or prevention of that particular condition, as well as use ofthe composition for the manufacture of a medicament for the treatment orprevention of that particular condition.

In some embodiments, aspects of the invention relate to compositions fordelivering a phosphodiesterase type 5 inhibitor and/or a salt thereof toa subject. In some embodiments, a composition comprises aphosphodiesterase type 5 inhibitor and/or a salt thereof in a hostilebiophysical environment for topical delivery to the skin of a subject.In some embodiments, a composition also comprises a nitric oxide donor.In some embodiments, a composition further comprises one or morecompounds that stabilize and/or otherwise promote the efficacy ofstorage and/or delivery (e.g., with or without a nitric oxide donor).

In some embodiments, compositions of the invention increase theefficiency of direct compound delivery to a target site by usingtransdermal delivery thereby significantly lowering the systemicexposure and reducing potential side effects. For example, a transdermaldelivery according to the invention can reduce systemic exposure to lessthan 10% (e.g., less than 5%, or between 0.1% and 1%, or even less) ofthe systemic exposure resulting from an oral dosage required foreffective delivery of the compound. For example, the systemic exposureof a phosphodiesterase type 5 inhibitor (e.g., sildenafil) that isdelivered topically according to the invention can be about 0.3% of thesystemic exposure resulting from oral formulations. Also, in someembodiments, compositions of the invention provide for unexpectedly highspeeds of action of the compound being delivered (e.g., relative to oraldelivery or other delivery techniques used for the compound).Accordingly, in some embodiments, aspects of the invention are usefulfor rapid therapy when delivery of a therapeutic amount of a compoundwithin a short period of time is required. Topical delivery formulationsdescribed herein can deliver a compound to a target tissue more rapidlythan an oral formulation, for example. Topical delivery formulationsalso allow for targeted local delivery of a therapeutically effectiveamount of compound without requiring a significant systemic increase inthe amount of compound. However, it should be appreciated that topicalformulations can be used for systemic delivery if so required.

One aspect of the present invention is generally directed to acomposition, e.g., a composition for topical delivery to the skin of asubject. In accordance with one set of embodiments, the compositionincludes a nitric oxide donor, a hostile biophysical environment, astabilization polymer, propylene glycol, a polysorbate surfactant, and aphosphodiesterase type 5 inhibitor and/or a salt thereof.

In another set of embodiments, at least about 80% by weight of thecomposition comprises water, at least one chloride salt, a nitric oxidedonor, a stabilization polymer, propylene glycol, a polysorbatesurfactant, and a phosphodiesterase type 5 inhibitor and/or a saltthereof.

The composition, in accordance with yet another set of embodiments,includes a nitric oxide donor, a hostile biophysical environment, and aphosphodiesterase type 5 inhibitor and/or a salt thereof.

According to still another set of embodiments, the composition comprisesor consists essentially of water, sodium chloride, a nitric oxide donor,glyceryl stearate, cetyl alcohol, magnesium chloride, squalane, astabilization polymer, isopropyl myristate, oleic acid, propyleneglycol, a polysorbate surfactant, and a phosphodiesterase type 5inhibitor and/or a salt thereof.

In yet another set of embodiments, the composition comprises each of thefollowing compounds at concentrations of no more than +20% of the statedconcentrations: water at a concentration of about 35% to about 55% byweight, sodium chloride at a concentration of about 2.5% to about 15% byweight, a nitric oxide donor at a concentration of about 2.5% to about15% by weight, glyceryl stearate at a concentration of about 4% to about10% by weight, cetyl alcohol at a concentration of about 4% to about 10%by weight, magnesium chloride at a concentration of about 0.1% to about5% by weight, squalane at a concentration of about 1% to about 8% byweight, a polysorbate surfactant at a concentration of about 0.2% toabout 2% by weight, isopropyl myristate at a concentration of about 0.1%to about 5% by weight, oleic acid at a concentration of about 0.1% toabout 5% by weight, propylene glycol at a concentration of about 1% toabout 10% by weight, a stabilization polymer at a concentration of about1% to about 10% by weight, and a phosphodiesterase type 5 inhibitorand/or a salt thereof at a concentration of about 1% to about 10% byweight. In some embodiments, a composition comprises approximately 5%(e.g., 1% to 15%, or more or less) by weight of inhibitor (e.g.,sildenafil or other inhibitor) in an oil/water emulsion furthercomprising about 10% sodium chloride, 5% potassium chloride, and about2.5% magnesium chloride. For example, the inhibitor may be aphosphodiesterase type 5 inhibitor and/or a salt thereof.

In some embodiments, the pH of a composition is optimized to ionize theinhibitor while remaining compatible with acceptable pH ranges forcontact with the skin (e.g., within a range of about pH 5 to about pH8). In some embodiments, a pH below 10 is sufficient to ionize aninhibitor such as sildenafil or related compounds. In some embodiments,a pH of 5-8 (+/−0.5) is effective. In some embodiments, a pH of 6.5(e.g., +/−0.5) is particularly effective. In some embodiments, a pH atleast about 1 pH unit above or below (e.g., at least about 2 pH unitsabove or below) the pKa of an inhibitor may be used, particularly if thepH is within the range of about pH 5.0-8.0 that is particularlycompatible for direct topical contact with skin. The inhibitor may be,for instance, a phosphodiesterase type 5 inhibitor and/or a saltthereof, or any inhibitor discussed herein.

According to aspects of the invention, a relatively high saltconcentration, for example at least about 2% (e.g., about 5%, about 10%about 15%, about 20% about 25%, about 25-50%, weight %) is useful toprovide a hostile biophysical environment that promotes transdermalmigration of an inhibitor (e.g., sildenafil). In some embodiments,emulsions described herein, for example, containing a stabilizationpolymer and/or a polysorbate surfactant and/or propylene glycol (or alow molecular weight glycol, or a polyglycol such as polyethylene glycolor other polyglycol—however it should be appreciated that glycols witheven numbers of carbons can be toxic, particularly for smaller glycolssuch as ethylene glycol and butylene glycol, and should be avoided orexcluded) are unexpectedly effective at stabilizing the inhibitor in thehigh salt composition in a form that remains effective for an extendedperiod—for example, retaining rapid transdermal delivery of theinhibitor for at least several weeks or months. In some cases, theinhibitor is a phosphodiesterase type 5 inhibitor and/or a salt thereof.

In some embodiments, a composition also includes a nitric oxide donor(e.g., L-Arg) that can be useful to increase local blood flow andfurther promote delivery of the compound. In accordance with another setof embodiments, the composition comprises a stabilization polymer,propylene glycol, a polysorbate surfactant, and a phosphodiesterase type5 inhibitor and/or a salt thereof.

In still another set of embodiments, at least about 80% by weight of thecomposition comprises water, at least one chloride salt, a stabilizationpolymer, propylene glycol, a polysorbate surfactant, and aphosphodiesterase type 5 inhibitor and/or a salt thereof.

The invention, in accordance with another aspect, is generally directedto a method. In one set of embodiments, the method is a method ofapplying any of the compositions described herein to a subject, e.g., tothe skin of a subject. The method, in accordance with another set ofembodiments, includes an act of applying, to a portion of the skin of asubject, a delivery vehicle comprising a phosphodiesterase type 5inhibitor and/or a salt thereof in a hostile biophysical environment.

The method, in yet another set of embodiments, includes an act ofapplying, to at least a portion of the skin of a subject, a compositioncomprising a nitric oxide donor, a hostile biophysical environment, astabilization polymer, propylene glycol, a polysorbate surfactant, and aphosphodiesterase type 5 inhibitor and/or a salt thereof.

In another aspect, the present invention encompasses methods of makingone or more of the embodiments described herein, for example, acomposition comprising a phosphodiesterase type 5 inhibitor. In stillanother aspect, the present invention encompasses methods of using oneor more of the embodiments described herein, for example, a compositioncomprising a phosphodiesterase type 5 inhibitor. In yet another aspect,the present invention encompasses various uses of a compositionincluding a phosphodiesterase type 5 inhibitor. For example, thecomposition may be used to treat erectile dysfunction.

In some embodiments, aspects of the invention relate to a patch thatcomprises a composition of the invention (e.g., with or without a nitricoxide donor, and with or without one or more stabilizing compounds). Insome embodiments, a composition is in the form of a cream or ointmentthat is incorporated into the patch. However, other configurations alsomay be used.

In some embodiments, aspects of the invention relate to methods andformulations for delivering a compound locally at a fraction of thesystemic dose required using oral delivery. In some embodiments, ahostile biophysical environment may be evaluated for enhancing localdelivery through a topical application. Depending on the therapeuticapplication, an appropriate delivery configuration (e.g., a combinationof compound concentration, hostile biophysical environment, cream,patch, etc.) can be used to reduce the systemic amount of the compoundrequired for an effective therapeutic application.

In some embodiments, aspects of the invention relate to reducing oravoiding the side effects (in males and in females where side effectshave caused the FDA to refuse approval) associated with systemic levelsof phosphodiesterase type 5 inhibitors required to produce a desiredlocal effect when administered orally. In some embodiments, aspects ofthe invention can be used to treat sexual dysfunction in males and/orfemales by providing a topical formulation of one or morephosphodiesterase type 5 inhibitors. The topical formulation can be usedto provide local levels that are effective (e.g., by applying topicallyto the male or female genitalia) without causing high systemic levelsthat are associated with the dosages required for effective oraladministration. In some embodiments, aspects of the invention provide atopical delivery formulation that is effective within about 5 minutes(e.g., within less than about 30, less than about 20, less than about15, less than about 10, or less than about 5 minutes) after topicalapplication as opposed to waiting for 30 minutes to 1 hour or more foran oral administration to have an effect.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control in theabsence of clear error. If two or more documents incorporated byreference include conflicting and/or inconsistent disclosure withrespect to each other, then the document having the later effective dateshall control.

DETAILED DESCRIPTION

The present invention generally relates to the transdermal delivery ofvarious compounds. In some aspects, transdermal delivery may befacilitated by the use of a hostile biophysical environment. One set ofembodiments provides a composition for topical delivery comprising aphosphodiesterase type 5 inhibitor and/or a salt thereof, andoptionally, a hostile biophysical environment and/or a nitric oxidedonor. In some cases, the composition may be stabilized using acombination of a stabilization polymer (such as xanthan gum, KELTROL® BTand/or KELTROL® RD), propylene glycol, and a polysorbate surfactant suchas Polysorbate 20, which combination unexpectedly provides temperaturestability to the composition, e.g., at elevated temperatures such as atleast 40° C. (at least about 104° F.), as compared to compositionslacking one or more of these.

According to aspects of the invention, compositions comprising arelatively high salt composition (e.g., high chloride content) areunexpectedly effective for topical delivery of a phosphodiesterase type5 inhibitor (e.g., sildenafil or other inhibitor, including saltsthereof). In some embodiments, a salt-enhanced delivery (e.g., in acomposition having at least 2% salt, at least 5% salt, at least 10%salt, at least 15% salt, or higher as described herein) is particularlyeffective when the pH of the composition is optimized to ionize thecompound being delivered (e.g., at least about 80%, at least about 90%,at least about 95%, or about 99% or more) is ionized. It should beappreciated that depending on the pKa of the compound and the pH of thecomposition, the ionized form may be anionic or cationic (e.g., due toprotonation). In some embodiments, a compound may contain severalionizable groups each having a different pKa. In some embodiments, it issufficient for at least 1, 2, or 3 of the groups to be ionized for thesalt-enhanced delivery to be effective. In some embodiments, anionizable group is sufficiently ionized if the pH of the composition isat least 1 pH unit, or at least 2 pH units (e.g., 1, 1-2, 2-3, or morepH units) below the pKa of the group and it is cationic (due toprotonation) below its pKa. Similarly, in some embodiments, an ionizablegroup is sufficiently ionized if the pH of the composition is at least 1pH unit, or at least 2 pH units (e.g., 1, 1-2, 2-3, or more pH units)above the pKa of the group and it is anionic (due to deprotonation)above its pKa. In some embodiments, the presence of magnesium chloride,for example at 0.1-5% by weight, can help stabilize composistionscontaining compounds with relatively high pKas (e.g., above 8.0, above9.0, above 10.0 or higher). In some embodiments, the pH of a compositionmay be maintained using a buffer. However, the pH of compositions of theinvention are surprisingly stable without a buffer. In some embodiments,a desired pH can be established by titrating the mixture with an acid(e.g., HCl) or a base (e.g., NaOH). The pH of the resulting composition(e.g., when formulated as an emulsion as described herein) can be stable(e.g., sufficiently for the composition to be effective for transdermaldelivery) for extended periods of time (e.g., weeks, months, or 1 ormore years).

According to other aspects of the invention, a high salt compositioncontaining a phosphodiesterase type 5 inhibitor is unexpectedly stablewhen formulated as an emulsion (e.g., a water in oil emulsion or an oilin water emulsion, for example, including one or more of a stabilizationpolymer and/or a polysorbate surfactant and/or propylene glycol (orother low molecular weight glycol, or a polyglycol) as describedherein). In some embodiments, the pH of the composition comprising theemulsion and high salt concentration is selected to ionize the compoundbeing delivered as described herein.

In some embodiments, topical delivery according to the invention (e.g.,topical delivery of phosphodiesterase type 5 inhibitor, for examplesildenafil) provides a surprisingly rapid effect (within about 1-5minutes). In contrast, an oral counterpart requires about 60 minutes ormore to produce an effect. Accordingly, aspects of the invention providemethods and compositions for delivering an effective treatment to asubject to treat or prevent erectile dysfunction. In some embodiments, atopical composition provided that can be applied to a genital region ofa female or male subject (e.g., the penis of a male subject) to treat anerectile dysfunction (e.g., promote an erection) within less than 60minutes, less than 45 minutes, less than 30 minutes, or less than 15minutes of application.

One aspect of the invention provides compositions for the topicaldelivery of substances such as pharmaceutical agents (e.g., drugs,biological compounds, etc.). The pharmaceutical agents may be applied tothe skin of a subject, e.g. a human, to aid in treatment of medicalconditions or diseases, and/or the symptoms associated thereof. In someembodiments, the invention provides for the treatment of medicalconditions or diseases and/or ailments using pharmaceutical agents (forexample, to treat a subject diagnosed with a medical condition ordisease, as described herein), and in some cases, the invention providesfor the delivery of a minimum amount of pharmaceutical agents to provideeffective levels of medication to an effected area topically whilelimiting side effects. In some cases, the effective dosage of thepharmaceutical agent may be lower than the effective dosage of thepharmaceutical agent when taken orally.

For example, in one set of embodiments, the pharmaceutical agent is aphosphodiesterase type 5 inhibitor and/or a salt thereof. Aphosphodiesterase type 5 inhibitor is a drug that blocks the degradativeaction of phosphodiesterase type 5 on cyclic GMP, e.g., in the smoothmuscle cells lining the blood vessels supplying the corpus cavernosum ofthe penis. Part of the physiological process of erection involves therelease of nitric oxide (NO) in vasculature of the corpus cavernosum asa result of sexual stimulation. NO activates the enzyme guanylatecyclase which results in increased levels of cyclic guanosinemonophosphate (cGMP), leading to smooth muscle relaxation in bloodvessels supplying the corpus cavernosum, resulting in increased bloodflow and an erection. Accordingly, PDES inhibitors inhibit thedegradation of cGMP by phosphodiesterase type 5, increasing bloodflow tothe penis during sexual stimulation.

Non-limiting examples of phosphodiesterase type 5 inhibitors include,but are not limited to, avanafil, lodenafil, mirodenafil (pKa of 6.0),sildenafil (or analogs thereof, for example, actetildenafil,hydroxyacetildenafil, or dimethylsildenafil), tadalafil (pKa of 18),vardenafil (pKas of 3.4, 6.7, 8.8, and 14), udenafil (pKa of 10.53),acetildenafil, or thiomethisosildenafil. The structures of thesecompounds are respectively shown below:

Accordingly, various aspects of the invention are directed tocompositions including a phosphodiesterase type 5 inhibitor fortransdermal delivery or topical application to a subject. Othercompounds such as salts or derivatives of phosphodiesterase type 5inhibitors (including salts or derivatives of the above compounds) arealso included in other embodiments; thus, it should be understood thatin any embodiment described herein using a phosphodiesterase type 5inhibitor, this is by way of example only, and other embodiments of theinvention are directed to phosphodiesterase type 5 inhibitor salts,phosphodiesterase type 5 inhibitor derivatives, etc., instead of and/orin addition to phosphodiesterase type 5 inhibitors.

Phosphodiesterase type 5 inhibitors or other pharmaceutical agents(e.g., salts or derivatives of phosphodiesterase type 5 inhibitors,etc.) may be present at any suitable concentration. For instance, insome cases, the pharmaceutical agent may be present at a concentrationof at least about 0.1%, at least about 0.3%, at least about 0.5%, atleast about 0.7%, at least about 1%, at least about 2%, at least about3%, at least about 4%, at least about 5%, at least about 6%, at leastabout 7%, at least about 7.5%, at least about 8%, at least about 9%, orat least about 10% by weight of the composition. In certain embodiments,the pharmaceutical agent may be present at a concentration of no morethan about 1%, no more than about 2%, no more than about 3%, no morethan about 4%, no more than about 5%, no more than about 6%, no morethan about 7%, no more than about 8%, no more than about 9%, no morethan about 10%, no more than about 12%, no more than about 15%, or nomore than about 20% by weight of the composition. In addition, thepharmaceutical agent may be present in native form and/or as one or moresalts. For example, if a phosphodiesterase type 5 inhibitor is present,it may be used in its native form, and/or as one or more salts, e.g.,the sodium salt, the potassium salt, the magnesium salt, the lysinesalt, the arginine salt, the lactate salt, or the citrate salt of aphosphodiesterase type 5 inhibitor, e.g., avanafil, lodenafil,mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetildenafil,thiomethisosildenafil, etc. For salt forms of the pharmaceutical agent,“by weight of the composition” includes the entire salt form of thepharmaceutical agent, e.g., the agent itself as well as any counterionssuch as sodium, potassium, etc. The amount of the pharmaceutical agentmay be determined in a composition, for example, using techniques suchas HPLC or HPLC/MS that are known to those of ordinary skill in the art.

Many phosphodiesterase type 5 inhibitors are readily commerciallyavailable. In some cases, the phosphodiesterase type 5 inhibitor may beobtained as a racemic mixture, for example, of tadalafil (e.g.,(R,R)-tadalafil, (R,S)-tadalafil, (S,R)-tadalafil, and (S,S)-tadalafil).However, in other cases, one of the enantiomers may be present in anamount greater than the other. For example, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, or at least about 95%of the phosphodiesterase type 5 inhibitor within the composition may bepresent as one of the enantiomers. Techniques for preparing orseparating racemic phosphodiesterase type 5 inhibitors are known; see,for example, Gao, et al., “Chiral Separation of Two Pairs of Enantiomersof Tadalafil by High-Performance Liquid Chromatography,” J. Chrornatogr.Sci., 45:540-543, 2007.

The composition may also comprise a nitric oxide donor in someembodiments, for example, L-arginine and/or L-arginine hydrochloride. Insome cases, such a nitric oxide donor may be used to increase localizedblood flow at the site where the composition is applied, which mayenhance delivery of the pharmaceutical agent. The nitric oxide donor maybe present at any suitable concentration within the composition. Forinstance, in some cases, the nitric oxide donor is present at aconcentration of at least about 1%, at least about 2%, at least about3%, at least about 4%, at least about 5%, at least about 6%, at leastabout 7%, at least about 7.5%, at least about 8%, at least about 9%, orat least about 10% by weight of the composition. In some cases, one ormore nitric oxide donors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitricoxide donors) may be used. In some cases, there may be no more than 3,5, 7, or 10 nitric oxide donors present within the composition.

A “nitric oxide donor,” as used herein, is a compound that is able torelease nitric oxide and/or chemically transfer the nitric oxide moietyto another molecule, directly or indirectly, for example, through abiological process. The nitric oxide donor may release nitric oxide intothe skin, and/or tissues such as muscles and/or elements of thecirculatory system in close proximity to the surface of the skin.Non-limiting examples of nitric oxide donors include arginine (e.g.,L-arginine and/or D-arginine), arginine derivatives (e.g., L-argininehydrochloride and/or D-arginine hydrochloride), nitroglycerin,polysaccharide-bound nitric oxide-nucleophile adducts,N-nitroso-N-substituted hydroxylamines,1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoate, etc., and/or anycombination of these and/or other compounds.

Besides L-arginine and L-arginine hydrochloride, other non-limitingexamples of nitric oxide donors include D,L-arginine, D-arginine, oralkyl (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, etc.) esters of L-arginine and/or D-arginine (e.g., a methylester, an ethyl ester, a propyl ester, a butyl ester, etc.) and/or saltsthereof, as well as other derivatives of arginine and other nitric oxidedonors. For instance, non-limiting examples of pharmaceuticallyacceptable salts include hydrochloride, glutamate, butyrate, orglycolate (e.g., resulting in L-arginine glutamate, L-arginine butyrate,L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate,etc.). Still other examples of nitric oxide donors includeL-arginine-based compounds such as, but not limited to, L-homoarginine,N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated L-arginine,nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,citrulline, ornithine, linsidomine, nipride, glutamine, etc., and saltsthereof (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.),and/or any combination of these and/or other compounds. Still othernon-limiting examples of nitric oxide donors include S-nitrosothiols,nitrites, 2-hydroxy-2-nitrosohydrazines, or substrates of various formsof nitric oxide synthase. In some cases, the nitric oxide donor may be acompound that stimulates endogenous production of nitric oxide in vivo.Examples of such compounds include, but are not limited to, L-arginine,substrates of various forms of nitric oxide synthase, certain cytokines,adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein,OH-arginine, or endothelein, and/or any combination of these and/orother compounds.

Accordingly, it should be understood that, in any of the embodimentsdescribed herein that describe L-arginine and/or L-argininehydrochloride, other nitric oxide donors may also be used instead, or incombination with, L-arginine and/or L-arginine hydrochloride, in otherembodiments of the invention.

In some cases, the concentration of the nitric oxide donor within thecomposition may be tailored to have a duration of effective treatment ofat least about 3 hours, at least about 5 hours, or at least about 8hours or more in certain instances. The duration may also be controlled,for instance, by controlling the concentration of a penetrating agentused in conjunction with the nitric oxide donor. Penetration agents arediscussed in detail herein. The actual concentration for a particularapplication can be determined by those of ordinary skill in the artusing no more than routine experimentation, for example, by measuringthe amount of transport of the nitric oxide donor as a function ofconcentration in vitro across cadaver skin or suitable animal models,skin grafts, synthetic model membranes, human models, or the like.

As a particular non-limiting example, in certain embodiments, nitricoxide is provided using L-arginine, for example, at a concentration ofat least about 0.5% by weight (wt % or w/v) of L-arginine (optionallywith one or more penetrating agents as discussed herein, for example, apenetrating agent able to create a hostile biophysical environment), atleast about 0.75 wt %, at least about 1 wt %, at least about 2 wt %, atleast about 3 wt %, at least about 5 wt %, at least about 7 wt %, atleast about 10 wt %, or at least about 15 wt %. The L-arginine may bepresent in a suitable delivery vehicle, such as a cream or a lotion.L-arginine may be particularly useful in some cases due to its lowtoxicity, its high solubility, and/or its low cost. Other examples ofnitric oxide donors are discussed in International Patent ApplicationNo. PCT/US2005/005726, filed Feb. 23, 2005, entitled “Topical Deliveryof a Nitric Oxide Donor to Improve Body and Skin Appearance,” by E. T.Fossel, published as WO 2005/081964 on Sep. 9, 2005, incorporated hereinby reference.

Without wishing to be bound to any theory, it is generally believed thatthe flow of the pharmaceutical agent across the skin may slow as itbuilds up within the tissue. Fick's first law of diffusion suggests thatwhen the concentration inside becomes substantially equal to thatoutside, passive flow stops. The increased local blood flow may preventor at least decrease the stoppage of the flow of the pharmaceuticalagent. Thus, when the composition is applied to the skin, thepharmaceutical agent exits the vehicle into the tissue more readily, asthe pharmaceutical agent is dispersed by flow and does not build up inconcentration in the tissue. Thus, in certain embodiments,pharmaceutical agents may be introduced into the skin, for example, aphosphodiesterase type 5 inhibitor and/or a salt or derivative of aphosphodiesterase type 5 inhibitor, such as avanafil, lodenafil,mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetildenafil,or thiomethisosildenafil. Accordingly, the composition may be deliveredlocally and/or systemically; initially, much of the delivery is at firstlocal (i.e., through the skin), but in some cases, the pharmaceuticalagents may also be distributed systemically, e.g., upon reaching theblood supply.

The composition may also comprise a hostile biophysical environment to aphosphodiesterase type 5 inhibitor in some embodiments. In a hostilebiophysical environment, the environment surrounding the pharmaceuticalagent (e.g., a phosphodiesterase type 5 inhibitor, etc.) may be suchthat the pharmaceutical agent is in a chemically and/or energeticallyunfavorable environment, relative to the skin (e.g., the chemicalpotential and/or the free energy of the pharmaceutical agent within thehostile biophysical environment is significantly greater than thechemical potential and/or the free energy of the pharmaceutical agentwithin the skin, thus energetically favoring transport into the skin),especially the stratum corneum.

Examples of such compositions are discussed in International PatentApplication No. PCT/US2005/013228, filed Apr. 19, 2005, entitled“Transdermal Delivery of Beneficial Substances Effected by a HostileBiophysical Environment,” by E. Fossel, published as WO 2005/102282 onNov. 3, 2005, incorporated herein by reference. Other techniques forhostile biophysical environments are discussed in detail herein.Accordingly, certain embodiments of the invention are generally directedto compositions for topical delivery to the skin of a subject comprisinga nitric oxide donor, a hostile biophysical environment, and apharmaceutical agent such as a phosphodiesterase type 5 inhibitor, or asalt or a derivative of a phosphodiesterase type 5 inhibitor, or thelike.

A hostile biophysical environment of the invention can comprise, invarious embodiments, high ionic strength, a high concentration ofosmotic agents such as ureas, sugars, or carbohydrates, a high pHenvironment (e.g., greater than about 7, greater than about 8, greaterthan about 9, greater than about 10, greater than about 11, greater thanabout 12, or greater than about 13), a low pH environment (less thanabout 5, less than about 4, less than about 3 or less than about 2),highly hydrophobic components, or highly hydrophilic components or othersubstances that cause an increase in the chemical potential and/or freeenergy of the pharmaceutical agent, or any combination of two or more ofthese and/or other compounds. A hydrophobic component may, in someembodiments, have an octanol-water partition coefficient of at leastabout 100, at least about 1000, at least about 10⁴, at least about 10⁵,or more in some cases. Similarly, a hydrophilic component may have anoctanol-water partition coefficient of less than about 0.01, less thanabout 10⁻³, less than about 10⁻⁴, or less than about 10⁻⁵ in some cases.

In some cases, the composition defines the biophysical hostileenvironment. In other cases, a pharmaceutical agent may be packaged insuch a way that it is carried into tissue and/or its charge isneutralized by derivitization and/or by forming a neutral salt. Examplesof biophysically hostile environments include, but are not limited to,high ionic strength environments (e.g., by the addition of ureas,sugars, carbohydrates, and/or ionic salts such as lithium chloride,sodium chloride, potassium chloride, calcium chloride, magnesiumchloride, choline chloride, sodium fluoride, lithium bromide, etc.), aswell as combinations of these and/or other agents, for instance at highionic strengths (for example, greater than about 0.25 M, greater thanabout 1 M, greater than about 2 M, greater than about 3 M, greater thanabout 5 M, greater than about 10 M, greater than about 15 M, greaterthan about 20 M, greater than about 25 M, etc., or in some cases,between about 0.25 M and about 15 M, between about 5 M and about 15 M,between about 10 M and about 15 M, etc.); high or low pH environments(e.g., by adding pharmaceutically acceptable acids or bases, forexample, such that the pH is between about 3 and about 7, between about3 and about 6, between about 3 and about 5, between about 4 and 8,between about 5 and about 8, between about 5 and 8.5, between about 7and about 11, between about 8 and about 11, between about 9 and about11, etc.); or highly hydrophobic environments (e.g., by decreasing watercontent and increasing lipid, oil and/or wax content of theenvironment). In some embodiments, the ionic strength is any amountgreater than two times the physiological ionic strength of blood. Theionic strength of a composition can be readily controlled in certainembodiments by controlling the amounts or concentrations of one or moreof the salts present in the composition, e.g., by controlling the amountof sodium chloride, magnesium chloride, choline chloride, etc., and/orother salts.

Other highly charged molecules such as polylysine, polyglutamine,polyaspartate, etc., or copolymers of such highly charged amino acidsmay also be used in certain embodiments to create the hostilebiophysical environment. Non-limiting examples of delivery vehicleswhich would be carried into tissue includes liposomes or emulsions ofcollagen, collagen peptides or other components of skin or basementmembrane. Non-limiting examples of neutralization of charge includedelivery of the pharmaceutical agent in the form or an ester or saltwhich is electronically neutral. In some embodiments, the hostilebiophysical environment may include any two or more of these conditions.For instance, the hostile biophysical environment may include high ionicstrength and a high pH or a low pH, a highly hydrophobic environment anda high pH or a low pH, a highly hydrophobic environment that includesliposomes, or the like.

A hostile biophysical environment may also be created in someembodiments by placing a pharmaceutical agent that is relatively highlycharged into a hydrophobic, oily environment such as in an oil-basedcream or lotion containing little or no water. Absorption may further beaided by combining the use of hostile biophysical environments with theuse of penetrating agents, as further described herein.

In one set of embodiments, the composition may be present as anemulsion. As known by those of ordinary skill in the art, an emulsiontypically includes a first phase (e.g., a discontinuous phase) containedwithin a second fluid phase (e.g., a continuous phase). Thepharmaceutical agent (e.g., a phosphodiesterase type 5 inhibitor) may bepresent in either or both phases. In addition, other materials such asthose described herein may be present in the same phase as thepharmaceutical agent.

In some embodiments, an emulsion may be prepared to contain a drug (orother pharmaceutical agent) of interest in a hostile biophysicalenvironment, and optionally one or more of a stabilization polymer,propylene glycol, and/or a polysorbate surfactant. An emulsion may alsocomprise a nitric oxide donor in some embodiments, for example,L-arginine and/or L-arginine hydrochloride.

In some embodiments, various aspects of the invention relate to methodsand compositions for preparing and/or manufacturing drug formulationsfor topical delivery. In one set of embodiments, the present inventionis generally directed to emulsions that contain one or more drugs orother pharmaceutical agents described herein for topical application. Insome embodiments, certain aspects of the invention are useful forpreparing emulsions that contain one or more drugs (or otherpharmaceutical agents) in a hostile biophysical environment. In someembodiments, the hostile biophysical environment is a high saltconcentration (e.g., a high concentration of one or more salts), forexample, as described herein.

In some embodiments, an emulsion is prepared by mixing a first aqueouspreparation (e.g., a water phase) with a second non-aqueous preparation(e.g., an oil or lipid phase). Drugs or other pharmaceutical agents thatare water-soluble may be added to the first aqueous preparation (e.g.,prior to mixing with the second non-aqueous preparation). Drugs or otherpharmaceutical agents that are water insoluble (or relatively waterinsoluble) may be added to the second non-aqueous preparation (e.g.,prior to mixing with the first aqueous preparation). Drugs or otherpharmaceutical agents that are partially water soluble may be added toone phase, or may be split between the two phases prior to mixing. Thesplit between the two phases will depend on the amount of drug (or otherpharmaceutical agent) that is being added, the composition (e.g., thenature and the amount of other chemicals or agents) of the first andsecond preparations, the pH, the temperature, other physical or chemicalfactors, and/or a combination thereof. For example, if a drug ofinterest is soluble at a 1% level in the aqueous (e.g., water or buffer)phase, but a 2% level of the drug is required in the emulsion, then thedrug may also be added to the non-aqueous (e.g., lipid) phase at a 1%level. In some embodiments, a drug that is less than 1% soluble in anaqueous phase is provided in the non-aqueous phase prior to mixing.However, it should be appreciated that other percentages and/or splitsbetween the two phases may be used.

In some embodiments, the pH of one or both of the first and secondpreparations is adjusted to optimize the solubility of the drug beingused. In some embodiments, a high salt concentration is used. In orderto prevent a high salt concentration from breaking down an emulsion, oneor more emulsifying agents may be used in some cases. In someembodiments, the mixing time may be adjusted to promote appropriatemixing and/or emulsion formation.

In some embodiments, the temperature of the first and/or secondpreparation may be controlled to promote solubility, mixing, and/oremulsion formation. In some embodiments, the temperature of one or bothpreparations and/or of the mixing may be set at 25° C. or higher (e.g.,30° C. or higher, 40° C. or higher, 50° C. or higher, 60° C. or higher,70° C. or higher, or 80° C. or higher). For example, the temperature maybe at between 30° C. and 90° C., between 40° C. and 80° C., at around50° C., at around 60° C., or at around 70° C.

It should be appreciated that methods and compositions of the inventionmay be used with any suitable drug or pharmaceutical agent. In someembodiments, for example, an oral drug may be formulated for topicaldelivery using one or more compositions or methods described herein. Atopical formulation may be useful to deliver a locally effective amountof a drug (or other pharmaceutical agent) to a subject (e.g., a human)without causing unwanted side effects associated with systemic levelsrequired for effectiveness when the drug is administered orally.Accordingly, a topical formulation may be useful to deliver an amount ofa drug that is sufficient to cause a desired effect (e.g., a therapeuticeffect) but that is lower than the total amount of the drug that wouldbe administered to a subject (e.g., a human) if it were provided orally.

Emulsions of the invention may be packaged using any suitable format(e.g., in a tube, a pump-actuated container, or any other suitableform), in certain embodiments of the invention. For example, in someembodiments, an emulsion may be added to a surface of a patch orbandage. The emulsion may also be applied to the skin of a subject as acream, gel, liquid, lotion, spray, aerosol, or the like.

Methods and compositions such as any of those discussed herein may beused to prepare a composition that is sterile or that has a lowmicrobial content, in some embodiments.

In some aspects of the invention, a composition of the invention isadministered to a subject using a delivery vehicle such as a cream, gel,liquid, lotion, spray, aerosol, or transdermal patch. In one set ofembodiments, a composition of the invention may be applied orimpregnated in a bandage or a patch applied to the skin of a subject. Insome embodiments, a patch has a skin contacting portion made of anysuitable material that is covered or impregnated with a cream oremulsion described herein, wherein the skin contacting portion may besupported by a backing, one or both of which may have an adhesivesegment or other configuration for attaching to the skin surface of asubject. A “subject,” as used herein, means a human or non-human animal.Examples of subjects include, but are not limited to, a mammal such as adog, a cat, a horse, a donkey, a rabbit, a cow, a pig, a sheep, a goat,a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), a guineapig, a hamster, a primate (e.g., a monkey, a chimpanzee, a baboon, anape, a gorilla, etc.), or the like. Such delivery vehicles may beapplied to the skin of a subject, such as a human subject. Examples ofdelivery vehicles are discussed herein. The delivery vehicle may promotetransfer into the skin of an effective concentration of the nitric oxidedonor and/or the pharmaceutical agent, directly or indirectly. Forinstance, the delivery vehicle may include one or more penetratingagents, as further described herein. Those of ordinary skill in the artwill know of systems and techniques for incorporating a nitric oxidedonor and/or a pharmaceutical agent within delivery vehicles such as acream, gel, liquid, lotion, spray, aerosol, or transdermal patch. Insome cases, the concentration of the nitric oxide donor, and/or apharmaceutical agent in the delivery vehicle can be reduced with theinclusion of a greater amount or concentration of penetrating agent, orincreased to lengthen the beneficial effect. In one set of embodiments,the nitric oxide donor and/or the pharmaceutical agent may be used inconjunction with an adjunct, such as theophylline (for example, at 10%weight by volume).

Other materials may be present within the delivery vehicle, for example,buffers, preservatives, surfactants, etc. For instance, the cream mayinclude one or more of water, mineral oil, glyceryl stereate, squalene,propylene glycol stearate, wheat germ oil, glyceryl stearate, isopropylmyristate, steryl stearate, polysorbate 60, propylene glycol, oleicacid, tocopherol acetate, collagen, sorbitan stearate, vitamin A and D,triethanolamine, methylparaben, aloe vera extract, imidazolidinyl urea,propylparaben, PND, and/or BHA.

As specific non-limiting examples, a cream may have one or more of(w/v): water (20-80%), white oil (3-18%), glyceryl stearate (0.25-12%),squalene (0.25-12%), cetyl alcohol (0.1-11%), propylene glycol stearate(0.1-11%), wheat germ oil (0.1-6%), polysorbate 60 (0.1-5%), propyleneglycol (0.05-5%), collagen (0.05-5%), sorbitan stearate (0.05-5%),vitamin A (0.02-4%), vitamin D (0.02-4%), vitamin E (0.02-4%),triethanolamine (0.01-4%), methylparaben (0.01-4%), aloe vera extract(0.01-4%), imidazolidinyl urea (0.01-4%), propylparaben (0.01-4%), BHA(0.01-4%), L-arginine hydrochloride (0.25-25%), sodium chloride(0.25-25%), magnesium chloride (0.25-25%), and/or choline chloride(0.25-25%). The percentages of each compound can vary (or the compoundmay be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

In another embodiment, the cream may include a pharmaceutical agent, forinstance, a phosphodiesterase type 5 inhibitor such as those describedherein, and one or more of the following, in any suitable amount: water(e.g., 20-80%), L-arginine hydrochloride (e.g., 0-25%), sodium chloride(e.g., 0-25%), potassium chloride (e.g., 0-25%), glyeryl steareate(e.g., 0-15%), cetyl alcohol (e.g., 0-15%), squalene (e.g., 0-15%),isopropyl mysterate (e.g., 0-15%), oleic acid (e.g., 0-15%), Tween 20(e.g., 0-10%), and/or butanediol (e.g., 0-10%). The percentages of eachcompound can vary (or the compound may be absent in some cases), forexample, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%, 20%, etc.

In some embodiments, the cream may include a pharmaceutical agent, andone or more ionic salts at a concentration at least sufficient toproduce a hostile biophysical environment with respect to thepharmaceutical agent. For example, the cream may include one or more of(w/v): a charged and/or hydrogen bonding entity (0.001-30%), cholinechloride (1-30%), sodium chloride (2-30%), and/or magnesium chloride(1-20% w/v). In another example, the cream may include one or more of(w/v): L-arginine hydrochloride (2.5-25%), choline chloride (10-30%),sodium chloride (5-20%), and/or magnesium chloride (5-20%). In stillanother example, the cream may include one or more of (w/v): creatine(0.001-30%), inosine (0.001-30%), choline chloride (1-30%), sodiumchloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1-25%),and/or theophylline (0.1-20%). In some cases, the cream may also containL-arginine hydrochloride (0-12.5% w/v) and/or theophylline (0-10% w/v).The percentages of each compound can vary (or the compound may be absentin some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, 20%, etc. In these examples, choline chloride,sodium chloride, and/or magnesium chloride can be used to provide a highionic strength environment.

In some embodiments, the composition may include an antioxidant, whichmay be able to reduce or inhibit the oxidation of other molecules withinthe composition. Examples of suitable antioxidants include, but are notlimited to, glutathione, vitamin C, and vitamin E as well as enzymessuch as catalase, superoxide dismutase and various peroxidases. Theantioxidant may be present in any suitable concentration. For example,the antioxidant may be present at a concentration of at least about0.1%, at least about 0.3%, at least about 0.5%, at least about 0.7%, atleast about 1%, at least about 2%, at least about 3%, at least about 4%,or at least about 5% by weight of the composition. In certainembodiments, the pharmaceutical agent may be present at a concentrationof no more than about 0.2%, no more than about 0.5%, no more than about1%, no more than about 2%, no more than about 3%, no more than about 4%,or no more than about 5% by weight of the composition.

Another set of embodiments is generally directed to compositions havingrelatively high temperature stability. For example, the composition maybe stable at elevated temperatures such as at least 40° C. (at leastabout 104° F.) for periods of time of at least about a day. In someembodiments, for instance, a composition of the present invention mayfurther include a stabilization polymer, propylene glycol, and apolysorbate surfactant. Non-limiting examples of stabilization polymersinclude xanthan gum, KELTROL® BT and/or KELTROL® RD; an example of apolysorbate surfactant is Polysorbate 20. Additional examples arediscussed herein.

Such a combination of components to create high temperature stabilityare surprising, since compositions involving any two of these components(but not the third) were found to lack such high temperaturestabilization properties. It is not currently known why this combinationof components is remarkably effective at facilitating relatively hightemperature stability of the compositions discussed herein, as thesecomponents are not known to participate in any significant chemicalreactions with each other, and high temperature stability is greatlyreduced when one of the components is removed. In addition, propyleneglycol is not known to work in pharmaceutical compositions as astabilizing agent.

For instance, in one set of embodiments, a composition may be determinedto be one that has high temperature stability by determining whether thecomposition exhibits phase separation over a relatively long period oftime, e.g., over at least an hour, at least about 2 hours, at least aday, at least about a week, at least about 4 weeks, etc. For example, insome embodiments, a composition is exposed to ambient temperature andpressure for at least 1 hour, and the composition is then analyzed todetermine whether the composition exhibits phase separation or a changein phase. A stable compound is one that exhibits no phase separation,whereas an unstable compound may exhibit phase separation. Suchstability may be useful, for example, for storage of the composition,transport of the composition, shelf life, or the like.

As used herein, a “stabilization polymer” is a polymer that comprisesxanthan gum, a xanthan gum derivative, and/or a xanthan gum equivalent,for example, KELTROL® BT and/or KELTROL® RD, KELZAN® XC, KELZAN® XCD,KELZAN® D, KELZAN® CC, XANTURAL® 180, XANTURAL® 75, or the like, all ofwhich can be obtained commercially from various suppliers. In someembodiments, combinations of these and/or other polymers are alsopossible. In some cases, the stabilization polymer is chosen to be onewhich is at least generally regarded as safe for use in humans. Inaddition, in certain embodiments, the stabilization polymer is producedsynthetically, and/or one which has been purified to some degree. Thestabilization polymer may have any suitable molecular weight, forexample, at least about 1 million, at least about 2 million, at leastabout 5 million, at least about 10 million, at least about 25 million,or at least about 50 million.

The stabilization polymer may be present at any suitable concentrationwithin the composition. For example, the stabilization polymer may bepresent at a concentration of at least about 0.1%, at least about 0.2%,at least about 0.3%, at least about 0.4%, at least about 0.5%, at leastabout 0.6%, at least about 0.7%, at least about 0.8%, at least about0.9%, or at least about 1% by weight of the composition. In someembodiments, the stabilization polymer may be present at a concentrationof no more than about 0.1%, no more than about 0.2%, no more than about0.4%, no more than about 0.6%, no more than about 0.8%, no more thanabout 1%, no more than about 2%, no more than about 3%, no more thanabout 4%, no more than about 5%, no more than about 7%, no more thanabout 10%, no more than about 12%, no more than about 15%, or no morethan about 20% by weight of the composition. In some cases, more thanone stabilization polymer may be present, and each stabilization polymermay be present in any suitable amount. As a specific example, in certainembodiments, the stabilization polymer consists essentially of KELTROL®BT and/or KELTROL® RD. In certain instances, the stabilization polymermay have a fixed ratio of KELTROL® BT and/or KELTROL® RD, for example,1:1 or 3:5 by weight. In another example, the KELTROL® BT may be presentat a concentration of about 0.3% by weight and the KELTROL® RD may bepresent at a concentration of 0.5% by weight of the composition, or oneor both of these may be present at one of the other concentrationsdescribed above. Combinations of these and/or other stabilizationpolymers are also contemplated in other embodiments, e.g., KELTROL® BTand xanthan gum, KELTROL® RD and xanthan gum, etc. In some cases,thickening agents can be used instead of, or in conjunction with astabilization polymer. Many thickening agents can be obtainedcommercially. Thickening agents include those used in the food industry,or are GRAS agents (generally regarded as safe), e.g., alginin, guargum, locust bean gum, collagen, egg white, furcellaran, gelatin, agar,and/or carrageenan, as well as combinations of these and/or otherstabilization polymers. It should thus be appreciated that, in thespecification herein, references to stabilization polymers, in otherembodiments, should be understood to also include thickening agents inconjunction or instead of stabilization polymers,

Propylene glycol can be obtained commercially, and can be present as anystereoisomer or racemic mixture of isomers. It may also be present atany suitable concentration. For instance, propylene glycol may bepresent at a concentration of at least about 1%, at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about 6%,at least about 7%, at least about 8%, at least about 9%, or at leastabout 10% by weight of the composition. In some embodiments, propyleneglycol may be present at a concentration of no more than about 2%, nomore than about 4%, no more than about 6%, no more than about 8%, nomore than about 10%, no more than about 12%, no more than about 15%, nomore than about 20%, or no more than about 25% by weight of thecomposition. In some cases, other glycols can be used in conjunction orinstead of propylene glycol, such as butylene glycol. Accordingly, itshould thus be appreciated that, in the specification herein, referencesto propylene glycol, in other embodiments, should be understood to alsoinclude other glycols (e.g., a low molecular weight glycol, or apolyglycol, as described herein) in conjunction or instead of propyleneglycol.

In addition, a polysorbate surfactant can also be present any suitableconcentration within the composition. For instance, in some cases, thepolysorbate surfactant may be present at a concentration of at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about 8%,at least about 9%, or at least about 10% by weight of the composition.In certain embodiments, the polylsorbate surfactant may be present at aconcentration of no more than about 2%, no more than about 4%, no morethan about 6%, no more than about 8%, no more than about 10%, no morethan about 12%, no more than about 15%, no more than about 20%, or nomore than about 25% by weight of the composition A “polysorbatesurfactant,” as used herein, is a surfactant comprising a polysorbate.For example, the surfactant may comprise sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan monooleate, or anothersorbitan salt. In some cases, the polysorbate surfactant has a molecularformula:

where w, x, y, and z are any suitable positive integers. w, x, y, and zmay also each be independently the same or different. In one set ofembodiments, w+x+y+z is 20 (e.g., as in Polysorbate 20). In some cases,other polymeric sugars can be used instead of, or in conjunction with, apolysorbate surfactant. Thus, it should be appreciated that, in thespecification herein, references to a polysorbate surfactant are by wayof example, and in other embodiments, it should be understood thatreferences to a polysorbate surfactant may include other polymericsugars in conjunction or instead of a polysorbate surfactant.

In some cases, the composition may have a fixed ratio of thestabilization polymer to propylene glycol to the polysorbate surfactant.For instance, the ratio of these may be about 1:1:1, about 1:6:3, about1:6:2, about 1:7:2, about 1:7:3, about 1.5:1:1, about 1.5:6:3, about1.5:6:4, about 1:6:2.5, about 1:6.25:2.5, about 1:6.25:2.5, etc. Asmentioned above, such ratios may be useful, in certain embodiments ofthe invention, in providing temperature stability to the composition.

In certain aspects of the invention, a pharmaceutical agent may becombined with a penetrating agent, i.e., an agent that increasestransport of the pharmaceutical agent into the skin, relative totransport in the absence of the penetrating agent. In some embodiments,the penetrating agent may define and/or be combined with a hostilebiophysical environment. Examples of penetrating agents includeoleoresin capsicum or its constituents, or certain molecules containingheterocyclic rings to which are attached hydrocarbon chains.

Non-limiting examples of penetrating agents include, but are not limitedto, cationic, anionic, or nonionic surfactants (e.g., sodium dodecylsulfate, polyoxamers, etc.); fatty acids and alcohols (e.g., ethanol,oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g.,benzilonium bromide, oxyphenonium bromide); alkanones (e.g., n-heptane);amides (e.g., urea,

N,N-dimethyl-m-toluamide); fatty acid esters (e.g., n-butyrate); organicacids (e.g., citric acid); polyols (e.g., ethylene glycol, glycerol);sulfoxides (e.g., dimethylsulfoxide); terpenes (e.g., cyclohexene);ureas; sugars; carbohydrates or other agents. In certain embodiments,the penetrating agent includes a salt, e.g., as described herein.

Thus, another aspect of the invention provides for the delivery ofpharmaceutical agents (e.g., drugs, biological compounds, etc.) into thebody, and such treatments may be systemic or localized, e.g., directedto a specific location of the body of a subject, such as the head, oneor more specific muscles, an arm, a leg, the genitals, etc., dependingon the specific application.

In one set of embodiments, pharmaceutical agents are introduced to aidin treatment of medical conditions or diseases, and the symptomsassociated thereof. In some embodiments, the invention provides for thetreatment of medical conditions or diseases and/or ailments usingpharmaceutical agents (for example, to treat a subject diagnosed with amedical condition or disease), and in some cases, the invention providesfor the delivery of a minimum amount of pharmaceutical agents to provideeffective levels of medication to an effected area topically whilelimiting side effects. In some cases, the effective dosage of thepharmaceutical agent may be lower than the effective dosage of thepharmaceutical agent when taken orally. Other embodiments of theinvention provide methods for treating erectile dysfunction.Accordingly, in some embodiments, a composition may be topically appliedto a specific location of the body, e.g., to the penis. Also, in certaincases, a composition as described herein may be used in the preparationof a medicament for treatment of erectile dysfunction, or other diseasesor conditions as discussed herein.

In another aspect, the present invention is directed to a kit includingone or more of the compositions discussed herein. A “kit,” as usedherein, typically defines a package or an assembly including one or moreof the compositions of the invention, and/or other compositionsassociated with the invention, for example, as described herein. Each ofthe compositions of the kit may be provided in liquid form (e.g., insolution), or in solid form (e.g., a dried powder). In certain cases,some of the compositions may be constitutable or otherwise processable(e.g., to an active form), for example, by the addition of a suitablesolvent or other species, which may or may not be provided with the kit.Examples of other compositions or components associated with theinvention include, but are not limited to, solvents, surfactants,diluents, salts, buffers, emulsifiers, chelating agents, fillers,antioxidants, binding agents, bulking agents, preservatives, dryingagents, antimicrobials, needles, syringes, packaging materials, tubes,bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps,patches, containers, and the like, for example, for using,administering, modifying, assembling, storing, packaging, preparing,mixing, diluting, and/or preserving the compositions components for aparticular use, for example, to a sample and/or a subject.

A kit of the invention may, in some cases, include instructions in anyform that are provided in connection with the compositions of theinvention in such a manner that one of ordinary skill in the art wouldrecognize that the instructions are to be associated with thecompositions of the invention. For instance, the instructions mayinclude instructions for the use, modification, mixing, diluting,preserving, administering, assembly, storage, packaging, and/orpreparation of the compositions and/or other compositions associatedwith the kit. In some cases, the instructions may also includeinstructions for the delivery and/or administration of the compositions,for example, for a particular use, e.g., to a sample and/or a subject.The instructions may be provided in any form recognizable by one ofordinary skill in the art as a suitable vehicle for containing suchinstructions, for example, written or published, verbal, audible (e.g.,telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) orelectronic communications (including Internet or web-basedcommunications), provided in any manner.

In some embodiments, the present invention is directed to methods ofpromoting one or more embodiments of the invention as discussed herein,for example, methods of promoting the making or use of compositions suchas those discussed above, methods of promoting kits as discussed above,or the like. As used herein, “promoted” includes all methods of doingbusiness including, but not limited to, methods of selling, advertising,assigning, licensing, contracting, instructing, educating, researching,importing, exporting, negotiating, financing, loaning, trading, vending,reselling, distributing, repairing, replacing, insuring, suing,patenting, or the like that are associated with the systems, devices,apparatuses, articles, methods, compositions, kits, etc. of theinvention as discussed herein. Methods of promotion can be performed byany party including, but not limited to, personal parties, businesses(public or private), partnerships, corporations, trusts, contractual orsub-contractual agencies, educational institutions such as colleges anduniversities, research institutions, hospitals or other clinicalinstitutions, governmental agencies, etc. Promotional activities mayinclude communications of any form (e.g., written, oral, and/orelectronic communications, such as, but not limited to, e-mail,telephonic, Internet, Web-based, etc.) that are clearly associated withthe invention.

In one set of embodiments, the method of promotion may involve one ormore instructions. As used herein, “instructions” can define a componentof instructional utility (e.g., directions, guides, warnings, labels,notes, FAQs or “frequently asked questions,” etc.), and typicallyinvolve written instructions on or associated with the invention and/orwith the packaging of the invention. Instructions can also includeinstructional communications in any form (e.g., oral, electronic,audible, digital, optical, visual, etc.), provided in any manner suchthat a user will clearly recognize that the instructions are to beassociated with the invention, e.g., as discussed herein.

The following documents are incorporated herein by reference:International Patent Application No. PCT/US98/19429, filed Sep. 17,1998, entitled “A Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel, published as WO 99/13717 on Mar. 25, 1999; U.S. patentapplication Ser. No. 11/587,323, filed Oct. 19, 2006, entitled“Transdermal Delivery of Beneficial Substances Effected by a HostileBiophysical Environment,” by E. T. Fossel, published as U.S. PatentApplication Publication No. 2008/0280984 on Nov. 13, 2008; and U.S.patent application Ser. No. 11/587,328, filed Oct. 19, 2006, entitled“Beneficial Effects of Increasing Local Blood Flow,” by E. T. Fossel,published as U.S. Patent Application Publication No. 2009/0105336 onApr. 23, 2009.

Also incorporated herein by reference are International PatentApplication No. PCT/US2005/005726, filed Feb. 23, 2005, entitled“Topical Delivery of a Nitric Oxide Donor to Improve Body and SkinAppearance,” by E. Fossel, published as WO 2005/081964 on Sep. 9, 2005;International Patent Application No. PCT/US2005/013228, filed Apr. 19,2005, entitled “Transdermal Delivery of Beneficial Substances Effectedby a Hostile Biophysical Environment,” by E. Fossel, published as WO2005/102282 on Nov. 3, 2005; International Patent Application No.PCT/US2005/013230, filed Apr. 19, 2005, entitled “Beneficial Effects ofIncreasing Local Blood Flow,” by E. Fossel, published as WO 2005/102307on Nov. 3, 2005; U.S. patent application Ser. No. 08/932,227, filed Sep.17, 1997, entitled “Topical Delivery of Arginine of Cause BeneficialEffects,” by E. T. Fossel, published as 2002/0041903 on Apr. 11, 2002;U.S. patent application Ser. No. 10/201,635, filed Jul. 22, 2002,entitled “Topical Delivery of L-Arginine to Cause Beneficial Effects,”by E. T. Fossel, published as 2003/0028169 on Feb. 6, 2003; U.S. patentapplication Ser. No. 10/213,286, filed Aug. 5, 2002, entitled “Topicaland Oral Arginine to Cause Beneficial Effects,” by E. T. Fossel,published as 2003/0018076 on Jan. 23, 2003; U.S. Pat. No. 5,895,658,issued Apr. 20, 1999, entitled “Topical Delivery of L-Arginine to CauseTissue Warming,” by E. T. Fossel; U.S. Pat. No. 5,922,332, issued Jul.13, 1999, entitled “Topical Delivery of Arginine to Overcome Pain,” byE. T. Fossel; U.S. Pat. No. 6,207,713, issued Mar. 27, 2001, entitled“Topical and Oral Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel; and U.S. Pat. No. 6,458,841, issued Oct. 1, 2002, entitled“Topical and Oral Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel.

In addition, incorporated by reference herein in their entireties areU.S. Provisional Patent Application Ser. No. 61/427,999, filed Dec. 29,2010, entitled “Treatment of Erectile Dysfunction and OtherIndications,” by E. T. Fossel; and U.S. Provisional Patent ApplicationSer. No. 61/428,213, filed Dec. 29, 2010, entitled “Methods andCompositions for Preparing Emulsions for Topical Drug Delivery,” by E.T. Fossel.

The following examples are intended to illustrate certain embodiments ofthe present invention, but do not exemplify the full scope of theinvention.

EXAMPLE 1

This prophetic example illustrates one method of preparing a transdermalformula of the invention including sildenafil, tadalafil, or vardenafil.The final composition is shown in Table 1. Of course, those of ordinaryskill in the art will understand that percentages other than the oneslisted below are also possible, according to other embodiments of theinvention.

TABLE 1 Ingredient % w/w Water 35-55 Sodium Chloride 2.5-15  L-ArginineHydrochloride 2.5-15  Sildenafil, Tadalafil, or Vardenafil  1-10Glyceryl Stearate (SE)  4-10 Cetyl Alcohol  4-10 Magnesium Chloride0.1-5   Squalane 1-8 Xanthan Gum 0.2-2   Isopropyl Myristate 0.1-5  Oleic Acid 0.1-5   Propylene Glycol  1-10 Polysorbate-20 0.1-5 

To prepare the formulation in this example, sodium chloride, potassiumchloride, L-arginine and sildenafil, tadalafil, or vardenafil were mixedin water, then heated to 74° C. with rapid mixing. In a separatecontainer, the remaining ingredients were mixed together and heated to74° C. The other ingredients were then added to the water phase at 74°C. with rapid mixing. The mixture was then cooled to room temperaturewith continued mixing. At this point, an emulsion formed with arelatively thin consistency. The emulsion was then homogenized at highspeed at room temperature to thicken the consistency.

EXAMPLE 2

Initially, it should be appreciated that the compositions described inthis example for the first aqueous and second non-aqueous preparationsfor use with ibuprofen may be used for other drugs or otherpharmaceutical agents such as those described herein (e.g., aphosphodiesterase type 5 inhibitor), or may be modified to containequivalent or similar compounds (or a subset thereof) for use withdifferent drugs or other pharmaceutical agents , and each drug or otherpharmaceutical agent may individually be provided in the firstpreparation, the second preparation, or both.

Ibuprofen sodium salt is water soluble at pH 7.0 and is added to thewater phase. Any suitable ibuprofen salt may be used. For example, acommercially available ibuprofen salt may be used. In some embodiments,an ibuprofen preparation is manufactured to have the following relativecomposition (Table 2).

TABLE 2 Ingredient Quality % w/w Water USP 40.9 Sodium Chloride USP 10.0L-Arginine Hydrochloride USP 7.5 Ibuprofen USP 7.5 Sodium Hydroxide USP1.3 Glyceryl Stearate (SE) 7.0 Cetyl Alcohol NF 7.0 Potassium ChlorideUSP 5.0 Squalane NF 4.0 Xanthan Gum FCC 0.8 Isopropyl Myristate NF 1.0Oleic Acid NF 1.0 Propylene Glycol USP 5.0 Polysorbate-20 NF 2.0

The basic manufacturing process is to form an emulsion by mixing a waterphase and an oil phase at elevated temperature with rapid mixing. Oncethe two phases are mixed the mixture is cooled to room temperature.While cooling is being accomplished homomixing is accomplished with avertical colloid mill. For example, in one set of embodiments, thefollowing manufacturing steps can be used:

Step 1: disperse xanthan gum in the propylene glycol and water and mixto fully hydrate.

Step 2: To the above mixture add ibuprofen and sodium hydroxide toproduce sodium ibuprofen, add sodium chloride, potassium chloride and1-arginine HCl. Heat this mixture to 75° C. to 80° C.

Step 3: Add glyceryl stearate SE, cetyl alcohol, squalane, isopropylmyristate, oleic acid and polysorbate-20 and heat this mixture to 75° C.to 80° C.

Step 4: Combine the mixtures produced in Step 2 and Step 3 and mix wellmaintaining temperature.

Step 5: Cool the mixture of Step 4 to 25° C. to 30° C. while circulatingthrough the vertical colloid mill.

The resulting smooth emulsion has a pH of 6.50 to 7.50. In some cases,the preparation can be manufactured under conditions to minimizemicrobial content (e.g., completely sterile or with a microbiologicalcontent of less than about 100 CFU/g).

In some embodiments, a transdermal ibuprofen cream is packaged in 100 ml“Magic Star Dispensers” which are airless pumps. The pump dispenses 1.45ml with each depression of the pump head.

Similar procedures may be used for preparing emulsions of othercompounds described herein. In some embodiments, the compound is addedto the oil phase prior to mixing with the aqueous phase. In someembodiments, the compound is added to the aqueous phase prior to mixingwith the oil phase.

EXAMPLE 3

Use of a topical sildenafil composition:

A 66 year old male with erectile dysfunction was given a creamcontaining 5% sildenafil in an oil/water emulsion to which was added 10%sodium chloride, 5% potassium chloride and 2.5% magnesium chloride. ThepH was 6.5. 15 minutes before initiating sexual activity he applied 1gram of cream to his penis and gently rubbed it in until absorbed. Uponengaging in sexual activity he achieved a full and functional erectionand sexual activity proceeded until successfully concluded.

The formula for the topical composition that was used for sildenafil isprovided in Table 3 below (shown as % weight). It should be appreciatedthat the relative amounts of each component may be varied (e.g., byabout 10%) in some embodiments. It also should be appreciated that thistopical composition may be used for other inhibitors (e.g., one or moreexamples of phosphodiesterase type 5 inhibitors including, but notlimited to, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil,udenafil, acetildenafil, or thiomethisosildenafil). In some embodiments,the active compound (e.g., sildenafil) may be added to the oil phaseprior to mixing with the aqueous phase. However, other compounds may beadded to the aqueous phase prior to mixing with the oil phase.

TABLE 3 Ingredient % by weight purified water 41 propylene glycol 5xanthum gum 0.8 active ingredient 5 sodium chloride 10 potassiumchloride 5 magnesium chloride 2.5 L-Arginine HCl 7.5 Glyceryl StearateSE 6.5 Cetyl Alcohol 6.5 Squalane 3.5 Isopropyl Myrstate 2 Oleic Acid 2Polysorbate 20 2

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is:
 1. A composition for topical delivery to the skin ofa subject, the composition comprising: a hostile biophysicalenvironment; a stabilization polymer; propylene glycol; a polysorbatesurfactant; a phosphodiesterase type 5 inhibitor and/or a salt thereof;and, optionally, a nitric oxide donor. 2-169. (canceled)